Department of Chemical Biology of Glycans and Lipids
Groups in the department:
Glycan specificity of galectin-1 depends on its modular organization, despite the identity of the modules
The variants of recombinant galectin-1 where carbohydrate-binding domains are organized differently from the native protein were studied here. The native protein has two domains are connected from head to tail in conjunction. We also have studied two-domain variants but with additional short and long spacer and four-domain ones. It turned out that two-domain constructs selectively lose the ability to bind some canonical glycans-ligands of galectin-1. The same was observed in case of galectin-3.
Enzyme-responsive liposomes with phospholipidic colchicinoids
New phospholipidic prodrugs of colchicinoids were synthesized for incorporation into bilayer of enzyme-responsive liposomes. The prodrug design takes into account the structure of the substrate-binding site of target enzyme, phospholipase A2 (PLA2), and the lateral pressure profile inside the bilayer. This allowed for minimal distortions of the lipid packing by the colchicinoid prodrugs and submicromolar cytotoxicity of the liposome carriers.
- (2019). Phospholipidic Colchicinoids as Promising Prodrugs Incorporated into Enzyme-Responsive Liposomes: Chemical, Biophysical, and Enzymological Aspects. Bioconjug Chem 30 (4), 1098–1113
Study of human natural antibodies glycocalix furing the fiest year of life revealed three aspects that are contradictory to current knowledge
Not all maternal IgG are detected in babies; dome specificities are absent till the age of 12 months. Thus, a mechanism preventing their migration through placenta possibly exists.
Babies fed by breast milk have less anti-glycan antibodies. In other words ‘unnatural’ feeding is accompanied by too early appearing of antibodies
It has been considered that at the age of 2 months maternal IgG slready are absent in babies. We observe that their level st this age is only two times lower, i.e. it rests considerable.
Influence of stabilizing components in the lipid bilayer on the integrity of antitumor liposomes loaded with lipophilic prodrug, in human serum
We compared the effect of different amphiphiles in lipid bilayer on the integrity of 100-nm-liposomes loaded with lipophilic prodrug of chemotherapeutic agent melphalan, in human serum. Using fluorescence methods phosphatidylinositol was shown to protect fluid phase lipid bilayer based upon egg phosphatidylcholine at least for 4 hours, while ganglioside GM1 or a conjugate of carboxylated oligoglycine with phosphatidylethanolamine up to 24 hours. At the same time, polyethylene glycol (2000 Da) conjugated with dipalmitoylphosphatidylethanolamine (PEG-lipid) promoted degradation of liposomes, so that lipids began to exit fluid phase membrane, while gel phase membrane with less than 10 mol % of PEG-lipid was immediately cracked. Cholesterol-containing bilayers of condenced liquid ordered phase, supplemented with sufficient amounts of the PEG-lipid, showed good stability in serum. The above effects should be accounted when using lipophilic conjugates of PEG in the composition of supramolecular drug delivery systems devoid of covalent bonds, such as liposomes, lipid nanospheres, or micelles.
- (2018). Influence of stabilizing components on the integrity of antitumor liposomes loaded with lipophilic prodrug in the bilayer. Colloids Surf B Biointerfaces 166, 45–53
Supramers on the base of amphiphillic molecules lipid-oligopeptide-biotin
It was found that oligopeptides with terminal lipid and biotin fragments are able to form micelle-like supramers (globules) in an aqueous solution. Using optical spectroscopy, atomic-force and electron microscopy, as well as small-angle X-ray scattering and computer simulation, it was shown that the globules are very uniform in size (about 14.6 nm). It was found that globules have the core/shell structure. The core contains lipid and part (up to 90%) of the biotin fragments. The polar oligopeptide spacer folds back upon itself and predominantly places the biotin reside inside the globule. But the part ( <10%) of biotin residues is exposed outside, and can be used for the selective attachment of specified molecules. Micelle-like supramers containing compounds that are natural to a living organism can become the basis for new types of carriers for targeted drug delivery.
New fluorescent probes to research the structure and functions of membranes
The use of anthrylvinyl-perylenoyl FRET-pair of phospholipid probes revealed the existence of regulatory interaction site(s) on the surface of ceramide-1 phosphate transfer protein that are specific to the polar head groups of phosphoglycerides in the lipid membrane. This finding delineates new differences between Glycolipid Transfer Proteins superfamily members that are specific for C1P versus glycolipid . By means of new BODIPY FRET-pair of phosphatidylcholine probes, it was shown that heterodimeric V. nikolskii phospholipases A2 induce aggregation and stacking of negatively charged lipid bilayers ; this may be one of the mechanisms of PLA2 biological activity. A novel combination of FRET between BODIPY-ganglioside probes and Monte Carlo simulations (MC-FRET) identified directly 10 nm large nanodomains (rafts) composed of sphingomyelin and cholesterol in liquid-disordered model membranes that mimic the cytoplasmic membrane; the nanodomains are also fluid and disordered .
- (2017). Heterodimeric V. nikolskii phospholipases A2 induce aggregation of the lipid bilayer. Toxicon 133, 169–179
- (2017). Phosphatidylserine stimulates ceramide 1-phosphate (C1P) intermembrane transfer by C1P transfer proteins. J Biol Chem 292 (6), 2531–2541
- (2017). Lipid Driven Nanodomains in Giant Lipid Vesicles are Fluid and Disordered. Sci Rep 7 (1), 5460
Liposomal formulation of a methotrexate lipophilic prodrug: interactions with tumor cells and studies in vivo
Previously, we developed a formulation of widely used cytostatic agent methotrexate incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug). Here, we first studied interactions of MTX-DG liposomes with various human and mouse tumor cell lines using fluorescence techniques. Liposomes were labeled with fluorescent analogues of phosphatidylcholine and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies with inhibitors of liposome uptake and processing by cells demonstrated that the formulation utilized multiple mechanisms to deliver the prodrug inside the cell. According to our data, undamaged liposomes fuse with the cell membrane only 1.5–2 h after binding to the cell surface and then the components of liposomal bilayer enter the cell separately. The study of the time course of plasma concentration in mice showed that the AUC (area under the curve) of methotrexate generated upon intravenous injection of MTX-DG liposomes exceeded that of intact methotrexate 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen (only four low to middle-dose injections) resulted in lower toxicity and retarded lymphoma growth rate as compared to methotrexate.
- (2017). Liposomal formulation of a methotrexate lipophilic prodrug: Assessment in tumor cells and mouse T-cell leukemic lymphoma. Int J Nanomedicine 12, 3735–3749